PROJECT SUMMARY/ABSTRACT Dilated and ischemic cardiomyopathies represent prevalent causes of heart failure and cardiovascular mortality worldwide. While landmark clinical trials have led to the establishment of effective heart failure therapies and improved clinical outcomes, mortality rates remain high and many patients ultimately experience disease progression, highlighting the clinically unmet need to identify novel treatments. Myocardial recovery is an increasingly recognized outcome for a small but significant number of patients with heart failure. Patients who experience myocardial recovery have improved quality of life and survival. Based on these observations, myocardial recovery represents an achievable outcome and a potential new therapeutic target. However, the mechanisms that dictate recovery and ultimately determine why some patients recover cardiac function while others experience disease progression are poorly defined. Remarkably, children with heart failure demonstrate a significantly greater capacity for myocardial recovery compared to adults. To dissect the mechanisms that mediate myocardial recovery in this context, we developed a mouse model of acute heart failure and successfully recapitulated the observation that the pediatric heart has a robust capacity for tissue repair and functional recovery. Mechanistically, we discovered that the injured pediatric and adult heart harbor distinct primitive and definitive macrophage subsets and that these cells govern why pediatric and adult mice display differing pathologic responses and capacities to recover following tissue injury. Collectively, these experiments uncovered a previously unrecognized complexity within the innate immune system and have challenged the paradigm that all macrophages are derived from monocyte progenitors. While these observations are thought provoking and provide proof of principle that distinct macrophage lineages have the capacity to differentially orchestrate cardiac tissue repair and heart failure progression, it is unclear how these concepts apply to the chronically failing heart. The overarching goal of this proposal is to test the hypothesis that the chronically failing mouse and human heart contains evolutionarily conserved macrophage subsets derived from distinct developmental origins that orchestrate cardiac tissue repair and adverse remodeling, respectively. Specifically, we hypothesize that primitive macrophages preserve cardiac function by stimulating tissue repair, whereas definitive monocyte-derived macrophages promote heart failure progression through inflammation, resultant collateral damage, and subsequent adverse remodeling. Clinically, the identification of reparative and inflammatory cardiac macrophage populations and elucidation of the signaling pathways by which these cells exert their effects is likely to provide the necessary information to develop novel therapeutic strategies to limit disease progression and promote recovery of the failing heart.